Natural Killer (NK) cells have been proposed to play an important regulatory role in hematopoiesis and in adaptive immune responses, either through direct cellular interactions or by releasing lymphokines and other soluble factors. The overall objective of this project is to study the role of human NK cells in the regulation of hematopoiesis in physiological and pathological conditions. The underlying hypothesis of this proposal is that NK cells are engaged in the regulation of reactions against self to ensure homeostasis. Rejection of bone marrow graft and some pathological states of bone marrow failure, in which the role for NK cells was demonstrated, would be a consequence of an enhancement or pathological alterations of this physiological regulatory mechanism. The NK cell-mediated natural resistance to leukemia- lymphomas is probably another manifestation, in pathological conditions, of the homeostatic function of NK cells. In order to characterize the mechanisms of NK cell-mediated regulation of normal and pathological hematopoiesis we will: - analyze the ability of NK cells to produce lymphokines affecting hematopoiesis, both stimulatory and inhibitory, and study the regulation of their production by NK cells; - investigate the cellular interactions between NK cells and bone marrow cells, leading to inhibition of colony formation and to lymphokine production; - study the effect of NK cells and NK cell-derived factors on leukemic precursor cells; - dissect at tissue level or using multicellular culture systems the cellular and humoral interactions involving NK cells in the bone marrow from normal individuals or from patients with hematological disorders.